EP1581519A1 - Ondansetron forms and processes of making the same - Google Patents

Ondansetron forms and processes of making the same

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Publication number
EP1581519A1
EP1581519A1 EP03718690A EP03718690A EP1581519A1 EP 1581519 A1 EP1581519 A1 EP 1581519A1 EP 03718690 A EP03718690 A EP 03718690A EP 03718690 A EP03718690 A EP 03718690A EP 1581519 A1 EP1581519 A1 EP 1581519A1
Authority
EP
European Patent Office
Prior art keywords
ondansetron
base
melting endotherm
water
range
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03718690A
Other languages
German (de)
English (en)
French (fr)
Inventor
Raymond Jozef Hubertus Westheim
Frans Van Dalen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Publication of EP1581519A1 publication Critical patent/EP1581519A1/en
Withdrawn legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents

Definitions

  • the present invention is directed to solid state forms of ondansetron base and methods for making various forms.
  • Ondansetron is a pharmaceutically active agent ⁇ commonly used for the treatment of nausea and vomiting, particularly when associated with cancer chemotherapy treatments.
  • compositions sold under brand name ZOFRAN® by Glaxo
  • ondansetron is used as a free base in rapidly dissolvable tablets and as a hydrochloride salt in injections, tablets for oral administration and oral solutions.
  • Ondansetron is chemically named 1,2,3,9- tetrahydro-9-methyl-3- ( (2-methyl-lH-imidazol-lyl) methyl-4H- carbazol-4-one and has the following chemical structure:
  • the ondansetron molecule has one optically active carbon, it can exist as two different enantio ers or as a mixture thereof, i.e., as a racemate. Both enantiomers are pharmaceutically active, however only the racemate is marketed thus far.
  • Example 18 Other than the melting point property, which differs from example to example, little information is given regarding the solid state material.
  • Ondansetron base prepared by other methods have reported various melting points from 215°C up to 228.5°C. For example:
  • the melting point of a solid material may be affected by the purity of the substance (the impurities tend to decrease the melting temperature) and it is also known that presence of trace contaminants may affect the formation and properties of crystalline lattice of the solid compound, resulting in changes in the crystalline forms and solid state properties (solubility, colour etc.).
  • the ther odynamic and kinetic aspects associated with conditions of solid state formation e.g., temperature of crystal formation, rate of cooling, concentration and kind of the solvent, etc.
  • the crystal structure of the ondansetron base is not set forth in any of the above-mentioned patents and thus it is unclear if the variation in melting point is due to impurities, measuring techniques, or polymorphic structure.
  • a first aspect of the invention relates to a solid crystalline ondansetron having at least one of the following characteristics: a DSC melting endotherm peak greater than or equal to 240°C; a trace amount of a base or residue thereof comprising an alkali metal, an amine, an ammonium, or an ion thereof; or a water content of 1.3 to 1.5 wt% .
  • the ondansetron solid form having a melting endotherm peak of at least 240°C typically has a peak within the range of 240°C to 255°C and preferably has a first melting endotherm peak within the range of 240°C to 249°C and frequently has a second, higher melting endotherm peak, typically between
  • the ondansetron having a trace amount of a base or residue preferably contains 1 ppm to 1000 pp of the base or residue.
  • the base or residue is normally provided in the crystal structure by a neutralization process, which is described hereinafter, although such is not required.
  • the base or residue comprises sodium or a sodium ion.
  • the ondansetron forms can be anhydrous or hydrated.
  • a preferred form of ondansetron crystalline solid form contains 1.3 to 1.5 % of water by weight. In a substantially pure substance this corresponds to a hemi-hemihydrate form.
  • a further aspect of the present invention relates to a crystalline ondansetron base having a purity of at least 98% and being in the form of particles having a particle size not greater than 200 microns. Such a form is useful in making a variety of pharmaceutical dosage forms.
  • the ondansetron particles have a size within the range of 0.1 to 100 microns, more preferably within the range of 0.1 to 63 microns.
  • compositions comprising any of the above forms of ondansetron and a pharmaceutically acceptable excipient .
  • the composition is preferably a unit dosage form for treating nausea and/or vomiting.
  • a further aspect of the invention relates to a process, which comprises neutralizing an acid addition salt of ondansetron to liberate ondansetron free base; and precipitating the ondansetron free base from a liquid media.
  • this process produces form I ondansetron as is described in more detail hereinafter.
  • An additional aspect of the invention relates to a process which comprises dissolving ondansetron free base in a solvent and precipitating the dissolved ondansetron free base to form ondansetron having a melting point of greater than 240°C measured on DSC at 5°C/min.
  • this process produces form II ondansetron as is described in more detail hereinafter.
  • Fig. 1 shows a DSC curve for the material of Example 1.
  • Fig. 2 shows a XRPD pattern for the material of Example 1
  • Fig. 3 shows a DSC curve for the material of Example la.
  • Fig. 4 shows a XRPD pattern for the material of Example la.
  • Fig. 5 shows a DSC curve for the material of Example 2.
  • Fig. 6 shows a XRPD pattern for the material of Example 2.
  • Fig. 7 shows a DSC curve for the material of Example 3.
  • Fig. 8 shows a XRPD pattern for the material of Example 3.
  • ondansetron base may be isolated in several solid state forms. These forms differ from the form(s) recited in the above-mentioned patents in one or more respects.
  • the solid ondansetron forms of the present invention can be characterized by melting point, trace base or residue levels, and/or water content.
  • ondansetron has a melting endotherm peak, i.e. a melting point, of at least 240°C, preferably within the range of 240°C to 255°C.
  • a melting endotherm peak is determined using differential scanning calorimetry (DSC) at a heating rate of 5°C/min.
  • DSC differential scanning calorimetry
  • the ondansetron has two melting endotherm peaks wherein the first melting endotherm peak occurs at a temperature of 240°C or greater. In this embodiment, both peaks generally occur within the temperature range of 240°C to 255°C.
  • the first and second melting endotherm peaks are within the range of 240°C-249°C and 249°C-255°C, respectively.
  • the ondansetron solid form exhibits melting endotherm peaks at about 244°C and 253°C.
  • Another ondansetron form can be characterized by the presence of a trace amount of a base or residue thereof which comprises an alkali metal, an amine, an ammonium, or an ion thereof.
  • the base or its residue is preferably provided into the crystal/solid state form of the ondansetron as a result of forming the solid ondansetron by a neutralization process involving an ondansetron acid addition salt and a base.
  • the base is preferably one that is sufficiently strong to neutralize an ondansetron acid addition salt and thereby liberate ondansetron free base.
  • the residue of the base refers to a portion of a base, especially the post-neutralization product (s) thereof.
  • Either the actual base, such as sodium hydroxide or a residue thereof such as a sodium ion, e.g. a sodium salt, can be present in the solid ondansetron form of this embodiment of the present invention.
  • the base is an alkali metal-containing base, especially sodium or potassium hydroxide, more preferably sodium hydroxide.
  • the residue is all that is incorporated, i.e. a salt comprising sodium ion, potassium ion, etc.
  • a "trace" amount as used herein means up to 1 wt%, preferably from 0.1 ppm to 1500 ppm, and more preferably is 1 ppm to 1000 ppm.
  • the base or residue is generally considered as having an effect on the crystalline matrix and hence crystal structure.
  • the ondansetron solid forms having a trace amount of the above-mentioned base or residue generally have a melting endotherm within the above-described known range, i.e. around 224° to 235°C.
  • Two specific forms of ondansetron are designated herein as form I and form II.
  • Form I and form II have many different physical properties, such as in differential scanning calorimetry (DSC) or X-ray powder diffraction (XRPD) analysis, and thus may be identified or distinguished from one another by one or more properties.
  • Form I ondansetron exhibits an X-RPD peak pattern that substantially corresponds to Fig. 2.
  • “Substantially corresponds” is meant to cover variations/differences in curve or pattern that would not be understood by a worker skilled in the art to represent a difference in crystal structure, but rather differences in technique, sample preparation, etc.
  • the XRPD pattern shown in Fig 4 substantially corresponds to the pattern shown in Fig 2 even though it is not identical.
  • the DSC curve exhibits a single sharp melting/degradation endotherm ' having a peak of about 224°C - 234°C; their being some variation in the onset temperature and peak temperature.
  • An example of a DSC scan for form I is shown in Fig. 1.
  • Thermogravimetric analysis (TGA) reveals thermal degradation above 220°C -
  • the form I ondansetron is sufficiently stable during storage at ambient and elevated temperatures. It is sensitive to a solvent-induced conversion into a form II defined below by slurrying in some polar solvents, e.g. in methanol or water, while it is inert to the same slurrying or solvent treatment in non-polar solvents.
  • Form II ondansetron exhibits an X-RPD peak pattern that substantially corresponds to Fig. 6.
  • the XRPD shown in Fig 8 substantially corresponds to the pattern shown in Fig 6.
  • the DSC curve exhibits a first melting endotherm peak at 240°C or greater and typically comprises two, usually overlapping, melting endotherms. Typically, these endotherm peaks are about 244°C and 253°C, but may be also shifted to slightly lower temperatures.
  • An example of a DSC curve for form II ondansetron is shown in Fig. 3. TGA shows thermal degradation above 240-250°C.
  • Form II is stable at room temperature when stored in closed vial, however a partial conversion to Form I was observed during prolonged storage at 40°C/75% relative humidity (RH) .
  • Form II is resistant to a solvent-inducing conversion to form I at ambient temperature.
  • Solid ondansetron base may exist in various states of hydration.
  • An anhydrate form may be obtained by careful drying of the product, preferably under vacuum, at an enhanced temperature.
  • Such anhydrate form comprises no or neglible amounts (less than 0.5%) of water.
  • an ondansetron form of the present invention is an ondansetron hydrate comprising ondansetron and water wherein the amount of water relative to ondansetron is within the range of
  • ondansetron base is the hemi-hemi hydrate as this is formed under most precipitation conditions and is stable.
  • the above forms I or II are preferably hydrates containing 1.3-1.5% of water.
  • the solid ondansetron forms of the present invention can be formed by precipitation.
  • One process comprises neutralizing an acid addition salt of ondansetron to form ondansetron free base and precipitating the free base, sometimes referred to herein as the "neutralization process" .
  • This process is generally advantageous for forming ondansetron form I.
  • the acid addition salts of ondansetron include hydrochloride, hydrobromide, maleate, tartrate, mesylate, and tosylate, but are not limited thereto.
  • Any suitable base e.g., NaOH, KOH, amines, ammonium hydroxide, etc., for converting the ondansetron acid salt to ondansetron free base can be used to carry out neutralization.
  • the solvent system is monophasic, i.e. it comprises a single solvent or a mixture of mutually miscible solvents, in which the resulting ondansetron base is only sparingly soluble and may thus precipitate and be separated from the remaining liquid.
  • the solvent system is so selected that the starting ondansetron salt and the neutralization base are soluble in the solvent system, at least at an elevated temperature, but this is not required; i.e. a slurry of ondansetron acid addition salt can be used in the monophasic solvent system.
  • the solvent system should advantageously also dissolve the co-product of the reaction, i.e.
  • the solvent should also preferably dissolve the side-products and impurities, particularly coloured impurities, which are eventually present in the starting ondansetron salt.
  • Suitable solvent systems comprise water and mixtures of water with water-miscible organic solvents such as lower aliphatic alcohol (methanol, ethanol) , ketone (acetone, methyl isobutylketone ) or cyclic ether (dioxan, tetrahydrofuran) .
  • ondansetron salt is dissolved or suspended in one part of the solvent system and a solution or suspension of the neutralizing base in another part of the solvent system is added thereto portionwise until the reaction is completed.
  • the composition of both parts of the solvent system may be identical or different. Completion of the neutralization reaction may be monitored, e.g. by measuring pH, the optimum value being of about 6 to about 9, more preferably 8 - 9.
  • the precipitation of the ondansetron free base from the monophasic solvent system may be spontaneous or may be induced, e.g. by reducing the temperature of the solvent or by reducing the volume of the solution. This depends on the nature and amount of the solvent system and the proper mode, of precipitation may be easily found by ordinary set of experiments.
  • the temperature of contacting may be ambient, but, advantageously, the reaction mixture may be also heated, optionally up to reflux, and then cooled after the reaction is completed. In this way, a precipitate more easy to filter out may be formed.
  • an additional part of the solvent system, a contrasolvent is added after the neutralization reaction is completed.
  • the contrasolvent which is a solvent in which the ondansetron base is insoluble, assists the precipitation by initiating the precipitation, increasing the yield of the precipitation, or both.
  • the solvent system is biphasic.
  • the neutralisation reaction proceeds in a first, essentially aqueous phase and the product of the reaction is extracted into the second phase, which is immiscible with the first phase, while the rest of the reagents and the salt co-product remains in the first phase.
  • the ondansetron base is precipitated from the solution in the second phase as described above.
  • the "liquid media" from which the liberated ondansetron free base is precipitated can be the same liquid media that the neutralization reaction took place in, a modified solvent system, such as where solvent (s) are removed or contra-solvent (s) are added, etc., after neutralization, or an entirely different solvent system such as in a biphasic solvent system as described above.
  • the neutralization process is suitable for producing solid crystalline ondansetron having a trace amount of a base or residue as described above and/or for producing form I ondansetron.
  • a monophasic system comprising a mixture of water and ethanol in which ondansetron hydrochloride is used as the acid addition salt represents a preferred process.
  • Ondansetron solid forms can also be formed by precipitating dissolved ondansetron base.
  • ondansetron base such as isolated crude product
  • Xn a suitable solvent
  • the ondansetron is precipitated from the solution as an ondansetron solid form having a melting point of greater than 240°C measured on DSC. This melting point refers to the first melting endotherm in the DSC analysis.
  • the "dissolving" of ondansetron can be achieved by completing an ondansetron synthesis that results in the formation of ondansetron dissolved in the solvent as well as by dissolving solid ondansetron base in a solvent.
  • Suitable solvents include methanol, ethanol, chloroform or ethyl acetate/methanol mixtures.
  • the solution of ondansetron may optionally be treated or contacted with a suitable adsorption material, such as activated carbon, filtered, and cooled. The treatment preferably is carried out while the solution is hot, i.e. greater than 40°C.
  • Ondansetron base precipitates after cooling and is separated by conventional methods such as filtration or centrifugation, and dried. Typically this form is form II ondansetron, particularly when the crystalline product separates out from the solution under elevated temperatures of about 40°C and more. It is obtained also by a precipitation comprising contacting a solution of crude ondansetron base in a solvent, e.g.
  • Crude or purified ondansetron base may be used for conversion into a suitable acid addition salt by a process employing a contact of ondansetron base with corresponding acid in a suitable solvent.
  • the salt may be isolated in solid state.
  • a preferred salt is ondansetron hydrochloride.
  • the solid precipitate can be separated from the solution by conventional techniques, such as filtration, and is generally dried.
  • ondansetron having a purity of at least 98%, preferably at least 99%, more preferably at least 99.5%, and even at least 99.9% purity, can be formed by any the processes. Such a degree of purity is advantageous in itself as ondansetron is intended to be used as a pharmaceutical.
  • ondansetron base having a particle size smaller than 200 microns hereinafter " microcrystalline ondansetron”
  • microcrystalline ondansetron is more suitable in making pharmaceutical formulations.
  • microcrystalline ondansetron dissolves more rapidly in the liquid medium.
  • microcrystalline ondansetron produces more homogeneous compositions even when using processes that do not employ solvents for homogenization. Furthermore, the microcrystalline ondansetron releases more rapidly from the tablet composition.
  • Preferred particle sizes of microcrystalline ondansetron base for use in pharmaceutical final dosage forms is within the range of 0.1 to 200, more preferably 0.1 to 100, still more preferably 0.1 to 63 microns. At least 99% of the entire population of ondansetron particles should fall within these ranges. In some embodiments the particles are less than 20 microns, preferably less than 10 microns. For example, a population where 90% of the particles have a size of 2 microns or less.
  • a representative ondansetron base population meets the following criterion:
  • microcrystalline The particle size of the precipitated product may be controlled e.g. by the temperature regimen, nature of the solvent, concentration of the solution, etc. Proper production conditions may be found by an ordinary set" of experiments.
  • Microcrystalline ondansetron base may be formed by crystallization of a crude ondansetron base from a solvent as well. In particular, it may be formed by mixing a hot solution of ondansetron base with a cold contrasolvent, whereby the temperature of contact is 20°C or less, or by rapid cooling of an oversaturated solution of ondansetron base. Furthermore, microcrystalline product may be formed by performing the precipitation or crystallization in ultrasonic bath. Ondansetron base of desired small particle size may also be obtained by micronizing in suitable micronization equipment known in the art, optionally in combination with sieving.
  • Ondansetron base preferably microcrystalline ondansetron
  • a pharmaceutical composition, or a precursor thereof comprises any of the above mentioned ondansetron base forms including the known ondansetron base in the above-recited purity or particle size, with a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is not particularly limited and includes solid as well as liquid excipients and includes all of the excipients (categories and species) mentioned hereinafter with regard to the various compositional embodiments.
  • the composition may be formulated for parenteral administration, oral administration, rectal administration, transdermal administration and the like.
  • the compositions for oral administration may be solid or liquid.
  • Liquid compositions for parenteral administration may be prepared from the ondansetron base, particularly from microcrystalline base, by dissolution. The dissolution may be advantageously performed by suspending the base in water, and adding a suitable pharmaceutically acceptable acid that forms a soluble salt. Suitable acid is hydrochloric acid. The acid is preferably used in an equimolar amount.
  • the pH of the obtained solution may be imparted by an excess of an acid or by a pharmaceutically acceptable base. Preferred pH range is about 3-5.
  • the composition may comprise a suitable buffer system to preserve the chosen pH range.
  • the buffer system is a citrate buffer, i.e. a mixture of citric acid and sodium citrate.
  • the solution may comprise an isotonising agent and/or preservative. Suitable concentration of ondansetron in the liquid solution is from 0.1 to 10 mg/ml, preferably 2 - 4 mg/ml.
  • Liquid compositions for oral administration may be made for instance as disclosed in WO 96/15786, with the proviso that microcrystalline ondansetron base is the active ingredient and the solution also comprise a molar equivalent of a pharmaceutically acceptable acid.
  • the pharmaceutical dosage forms formulated from the compositions of the invention comprise a unit dose of ondansetron, i.e. the therapeutically effective amount of ondansetron for a single dose administration.
  • the preferred amount of the ondansetron base in the unit dose is from 0.1 to 150 mg, preferably 1, 2, 4, 8, 16, or 24 mg.
  • the unit dose in a tablet form advantageously comprise one piece of the tablet but it also may comprise a divided tablets or one or more smaller tablets (minitablets) administered at the same time. In the last case, several smaller tablets may be advantageously filled into a gelatin capsule to form a unit dose.
  • the unit dose of pellets in a capsule is advantageously contained in a single capsule.
  • the unit dose of the injection solution is advantageously one vial. Solution for oral administration are preferentially packed in a multidose package, the unit dose being taken out by a calibrated vessel.
  • Solid compositions for oral administration may exhibit rapid, normal or extended release of the active substance from the composition.
  • the solid pharmaceutical compositions comprising microcrystalline ondansetron base are preferably formulated into normal, immediate release tablets.
  • Preferred tablet forms are disintegrable tablets.
  • the tablets may comprise suitable inactive ingredients, i.e., excipients, such as filler (s) /diluent (s) , binder (s), disintegrant (s) , surfactant (s) , lubricant (s) etc. They may be produced by any standard tabletting technique, e.g. by wet granulation, dry granulation or direct compression. The tabletting methods that do not employ a solvent
  • dry processes are preferable and the microcrystallinity of the active substance assures excellent homogenity of the mixture and good physical properties for tabletting.
  • the dry granulation procedure comprises mixing the solid excipients (except lubricants), compacting the mixture in a compactor (e.g. a roller compactor), milling the compacted mass, screening the milled granules, mixing with a lubricant and compressing the mixture into tablets.
  • the direct compression procedure comprises mixing the solid excipients and compressing the uniform mixture into tablets .
  • Ondansetron base may be also formulated by melt granulation, i.e. combining the ondansetron with a meltable functional excipient (e.g. glyceryl behenate) whereby upon heating a granulate is formed in suitable equipment.
  • the granulae can be compressed into tablets, optionally with the addition of further excipients such as a lubricant.
  • the amount of the ondansetron base in a tablet is from 1 to 10%, preferably 2-5%, based on the total weight of the tablet.
  • Ondansetron base may be also blended into compositions that are suitable for being formulated into pellets by pelletization techniques known in the art.
  • a plurality of ondansetron base pellets comprising the single dose of ondansetron may be encapsulated into capsules made from pharmaceutically acceptable material, such as hard gelatin.
  • a plurality of pellets may be compressed together with suitable binders and disintegrants to a disintegrable tablet that, upon ingestion, decomposes and releases the pellets.
  • the plurality of pellets may be filled into a sachet.
  • solid oral compositions comprising ondansetron base have the following release profile: more than 80% of the active is released in 30 minutes, most preferably in 15 minutes, when measured by a paddle method of Ph.Eur at 50 rpm in 0.01M HC1 in a normal vessel.
  • the same release results are achieved when measured in a peak vessel according to Van Kel.
  • the microcrystalline ondansetron as defined above, is especially suitable.
  • Tablets or pellets may be coated by a suitable coating, which may be a film coat (dissolvable in stomach environment) or an enteric coat (not dissolvable in stomach environment) .
  • microcrystalline ondansetron can be formulated into rapidly disintegrable tablets, e.g. into tablets as described in USP 6063802.
  • A a 80 % water, citric acid, citrate, NaCl, b ondansetron base, c HCl, d 20% water
  • B a 80 % water , HCl, b ondansetron base, c citric acid, citrate, NaCl, d 20% water
  • composition per 1 g of tablet core Composition per 1 g of tablet core:
  • composition per 1 g of tablet core Composition per 1 g of tablet core:
  • Microcrystalline 251 mg cellulose Preg. maize starch 50 mg Magnesium stearate 5 mg Talc 5 mg
  • composition per 1 g of tablet core Composition per 1 g of tablet core:
  • composition per 1 g of tablet core Composition per 1 g of tablet core:

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Otolaryngology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP03718690A 2003-01-09 2003-03-14 Ondansetron forms and processes of making the same Withdrawn EP1581519A1 (en)

Applications Claiming Priority (3)

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US43878003P 2003-01-09 2003-01-09
US438780P 2003-01-09
PCT/EP2003/002745 WO2004063189A1 (en) 2003-01-09 2003-03-14 Ondansetron forms and processes of making the same

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US (1) US20040198794A1 (nl)
EP (1) EP1581519A1 (nl)
AU (2) AU2003222765A1 (nl)
DK (1) DK200300114U3 (nl)
FI (1) FI6164U1 (nl)
FR (1) FR2849852A1 (nl)
GB (1) GB2398566A (nl)
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ES2238001B1 (es) 2004-01-21 2006-11-01 Vita Cientifica, S.L. Nuevas formas polimorficas de ondansetron, procedimientos para su preparacion, composiciones farmaceuticas que los contienen y su uso como aantiemeticos.
WO2005108392A2 (en) 2004-05-07 2005-11-17 Taro Pharmaceutical Industries Ltd. Process for preparing ondansetron hydrochloride dihydrate having a defined particle size
EP1828141A4 (en) * 2004-10-26 2009-04-01 Ipca Lab Ltd STAINING METHOD FOR PREPARING THE ANTIEMETIC 1,2,3,9-TETRAHYDRO-9-METHYL-3 - [(2-METHYL) -1H-IMIDAZOLE-1-YL) METHYL] -4H-CARBAZOLE-4-ON

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AU2003222765A1 (en) 2004-08-10
DK200300114U3 (da) 2004-04-23
GB0306944D0 (en) 2003-04-30
US20040198794A1 (en) 2004-10-07
FI6164U1 (fi) 2004-03-15
WO2004063189A1 (en) 2004-07-29
AU2003203580A1 (en) 2004-07-29
FIU20030093U0 (fi) 2003-03-06
GB2398566A (en) 2004-08-25
NL1022893C2 (nl) 2004-07-13
FR2849852A1 (fr) 2004-07-16

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